Many conventional antimalarial agents are known for treating malaria in mammals. For example, U.S. Pat. Nos. 3,082,154 to Allan, 3,574,833 to Arnold et al, 3,663,693 to Slighter et al and 4,284,627 to Raether et al disclose known antimalarial agents and compositions. Known antimalarial agents include mefloquine (a 4-quinolinemethanol), chloroquine and quinine. However, the widespread eradication of malaria with conventional antimalarial agents such as chloroquine and the other recited agents does not appear possible owing to the emergence of malarial parasites which are resistant to conventional antimalarial agents. For example, chloroquine resistant Plasmodium falciparum, which first appeared in Columbia and Thailand in 1960, is rapidly spreading. In fact, by 1984, chloroquine resistant P. falciparum had rapidly spread to at least 15 countries in Eastern Asia and Oceania, 10 countries in South America and 15 countries in Africa south of the Sahara. While mefloquine first appeared to be effective for treating resistant malarial parasites such as the chloroquine resistant P. falciparum, treatment failures with mefloquine have been reported. Isolates of P. falciparum from Thailand have been shown in vitro to be resistant to mefloquine, chloroquine and quinine. In face, isolates of P. falciparum have demonstrated resistance to antimalarial drugs to which the parasite is not known to have been previously exposed. Similar patterns of cross resistance and multiple drug resistance have been observed during laboratory induction of drug resistance in cloned strains of P. falciparum. Accordingly, a need exists to provide compositions and methods for effectively treating malarial parasites, and particularly for treating malarial parasites which exhibit resistance to one or more conventional antimalarial agents.
Multiple drug resistance patterns have also been encountered in cancer chemotherapy treatments. Neoplastic cells have become resistant not only to the drug used in the chemotherapy treatment but also to other unrelated drugs. The basis for this resistance in neoplastic cells has been actively studied in the last decade, and recent studies suggest that enhanced active efflux prevents the drug to which the cell is resistant from reaching toxic levels within the cell cytosol. Additionally, it has recently been determined that various chemical compounds have the effect of inhibiting enhanced active efflux so that the drug can accumulate in the cell whereby drug resistance is reversed and the resistant cell becomes sensitive again. Among the chemical compounds which have the effect of inhibiting the active efflux of chemotherapy drugs from cancer cells are calcium channel blockers.